The metabolic significance of ATP-citrate lyase in cancer: insights into glutamine-fuelled citrate biosynthesis and tumour progression.

ATP-citrate lyase (ACLY) is a major metabolic enzyme involved in the citrate to acetyl-CoA conversion, connecting glycolysis with lipid biosynthesis. More evidence has been given for its cancer metabolic role, but its patterns of expression and prognostic value in various cancers remain unclear, particularly in the process of cancer metabolic reprogramming, a feature of cancer progression and drug resistance. We performed a pan-cancer analysis of ACLY expression in six tumour types, bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC), using public databases like TIMER, GEPIA, UALCAN, and cBioPortal. GEPIA and UALCAN were utilized for evaluating prognostic significance, and GEO datasets for external validation. ACLY was consistently overexpressed in reprogrammed cancers (BLCA, BRCA, KIRC, KIRP, and LIHC) (P < 0.05 to P < 0.001) but appreciably downregulated in KICH, a metabolically quiescent cancer. ACLY overexpression was associated with poor prognosis in LIHC and KICH (P = 0.011 and P = 0.0081, respectively) but surprisingly associated with better survival in KIRC (P < 0.0001). Genomic alterations in ACLY were rare (< 4%) across all cancers. The findings were validated by multiple GEO datasets: GSE41804 (LIHC), GSE 3167 (BLCA), GSE 22820 (BRCA), GSE 53757 (KIRC), GSE15641 (KIRP), and GSE15641 (KICH). Conclusion: ACLY expression agrees with the metabolic phenotype of most tumours and has different prognostic implications. Overexpression in metabolically active cancers and association with poor outcomes, namely in LIHC, emphasizes its potential for therapeutic targeting as a tumour metabolic status biomarker. Downregulation in KICH, on the other hand, agrees with evidence of metabolic stability in certain cancers. These findings might be used in the direction of metabolism-based therapeutic approaches and risk stratification in oncology.